Intravaginal ring

Abstract

The present invention relates to an intravaginal ring (1) a core (2) comprising a first ethylene-vinyl acetate copolymer (3) having a vinyl acetate content from 28 to 40 wt %, and at least 10 wt % of an estrogenic steroid (4) based on the weight of the core, and a sheath (5) comprising a second ethylenevinyl acetate copolymer (6) having a vinyl acetate content from 18 to 28 wt %, and at least 10 wt % of a progestational steroid (7) based on the weight of the sheath. Using the intravaginal ring according to the present the inventors have found that it is possible to attain independent and optimal release of the two active ingredients: an estrogenic steroid and a progestational steroid, without the need for complex assembly of parts and without the need to use sophisticated multi-layer extrusion technology.

1 . An intravaginal ring comprising
 a core ( 2 ) comprising a first ethylene-vinyl acetate copolymer ( 3 ) having a vinyl acetate content from 26 to 40 wt %, and an estrogenic steroid ( 4 ), and   a sheath ( 5 ) comprising a second ethylene-vinyl acetate copolymer ( 6 ) having a vinyl acetate content from 20 to 40 wt %, and at least 10 wt % of a progestational steroid ( 7 ) based on the weight of the sheath, and   wherein the sheath is the outer Layer of the intravaginal ring.   
     
     
         2 . An intravaginal ring according to  claim 1 , wherein the sheath comprises at least 15 wt % of the progestational steroid based on the weight of the sheath, preferably at least 20 wt %, and even more preferred at least 30 wt %. 
     
     
         3 . An intravaginal ring according to  claim 1 or 2 , wherein the sheath comprises 40 wt % or less of the progestational steroid based on the weight of the sheath, preferably 35 wt % or less. 
     
     
         4 . An intravaginal ring according to  any of the preceding claims , wherein the progestational steroid is dispersed and/or incorporated in the second ethylene-vinyl acetate copolymer in the form of particles, such as crystals. 
     
     
         5 . An intravaginal ring according to  any of preceding claims , wherein the estrogenic steroid is dissolved in the first ethylene-vinyl acetate copolymer at or below the saturation concentration of said estrogenic steroid at 25° C. 
     
     
         6 . An intravaginal ring according to any of the  claims 1 to 4 , wherein the estrogenic steroid is dispersed and/or incorporated in the first ethylene-vinyl acetate copolymer in the form of particles, e.g. crystals. 
     
     
         7 . An intravaginal ring according to  claim 6 , wherein the core comprises at least 10 wt % of the estrogenic steroid based on the weight of the core, preferably at least 15 wt % of, and even more preferred at least 20 wt %. 
     
     
         8 . An intravaginal ring according to  claim 4  or any of the claims  6  to  8  wherein the particles of the progestational steroid and optionally the estrogenic steroid in the second and optionally the first ethylene-vinyl acetate copolymer, have a particle size of between 3 μm and 40 μm, preferably between 8 μm and 24 μm, and even more preferred between 10 and 24 μm, as determined by laser diffraction. 
     
     
         9 . An intravaginal ring according to  any of the preceding claims , wherein the first ethylene-vinyl acetate copolymer has a vinyl acetate content of 26 wt %, 33 wt % or 40 wt %. 
     
     
         10 . An intravaginal ring according to  any of the preceding claims , wherein the second ethylene-vinyl acetate polymer has a vinyl acetate content of 24 wt %, 28 wt %, 33 wt % or 40 wt %. 
     
     
         11 . An intravaginal ring according to  any of the preceding claims , wherein the estrogenic steroid is estradiol 
     
     
         12 . An intravaginal ring according to  any of the preceding claims , wherein the progestational steroid is a selected from the group consisting of progestogen, etonogestrel, levonorgestrel, d-1-norestrel and norethindrone. 
     
     
         13 . An intravaginal ring according to  any of the preceding claims , wherein the thickness of the sheath is between 0.05 mm and 3 mm, preferably between 0.05 mm and 2 mm, more preferably between 0.1 mm and 2 mm and even more preferably between 0.1 mm and 0.6 mm. 
     
     
         14 . An intravaginal ring according to  any of the preceding claims , wherein the cross-sectional diameter of the core is from between 2 and 8 mm, more preferably between 3 mm and 6 mm and even more preferably from 4 mm to 5 mm. 
     
     
         15 . An intravaginal ring according to  any of the preceding claims , wherein the outer diameter of the intravaginal ring ranges from 45 mm to about 65 mm, preferably around 54 mm. 
     
     
         16 . A method of manufacturing the intravaginal ring according to any of the  claims 1-15 , said method comprises
 a. providing a core comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 26 to 40 wt %, and an estrogenic steroid,   b. providing a sheath of comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content from 20 to 40 wt %, and at least 10 wt % of an progestational steroid based on the weight of the sheath, and   c. co-extruding the core and sheath into a fiber, and   d. cutting the fiber into an appropriate length thereby providing a fiber element, and   e. combining the ends of fiber element to form the intravaginal ring.   
     
     
         17 . A method according to  claim 16 , wherein said method further comprises a cooling step in which the provided fiber from step c. is cooled to a temperature of about 20° C. in order to provide crystals of at least the progestational steroid in sheath. 
     
     
         18 . Use of the intravaginal ring according to any of the  claims 1-15  for providing a substantially zero-order release rate of the estrogenic steroid during a treatment period of at least 28 days. 
     
     
         19 . Use according to  claim 18 , wherein the average release rate of estradiol is from 80 μg/day to 160 μg/day during a treatment period of at least 28 days. 
     
     
         20 . Use according to  claim 18 or 19 , wherein the average release rate of progestogen is from 5 mg/day to 10 mg/day during a treatment period of at least 28 days.